The present invention relates generally to synthetic organic chemistry. More particularly, the invention relates to the Claisen rearrangement reaction and to a novel method of performing such reactions so as to give rise to chiral products. The invention finds utility in the fields of organic synthesis and stereospecific catalysis.
Since its discovery in 1912, the Claisen rearrangement has become one of the most powerfull tools for carbon-carbon bond formation in chemical synthesis. See, e.g., Claisen (1912) Chem. Ber. 45:3157; Enders et al. (1996) Tetrahedron: Asymmetry 7:1847; Blechert et al. (1989) Synthesis 71; Kallmerten et al. (1989) Stud. Nat. Prod. Chem. 3:323; Moody et al. (1987) Adv. Heterocycl. Chem. 42:203; and Ziegler et al. (1988) Chem. Rev. 88:1423. The Claisen reaction is a [3,3]-sigmatropic rearrangement, which involves the conversion of an allylic compound, generally an allylic vinyl ether, to an xcex1,xcex2-disubstituted, xcex1,xcex3-unsaturated carbonyl compound. The reaction may be illustrated as follows: 
Allylic aryl ethers also undergo a Claisen rearrangement to give ortho-allylphenols: 
Activation of Claisen reactions has traditionally been accomplished under thermal control, typically at temperatures of 200xc2x0 C. or more. Activation has also been achieved through the incorporation of cationic or anionic charge in the bond reorganization event (see Takai et al. (1981) Tetrahedron Lett. 22:3985; Takai et al. (1984) Bull. Chem. Soc. 51:446; Stevenson et al. (1982) Tetrahedron Lett. 23:3143; and Takai et al. (1984) Tetrahedron 40:4013; Arnold et al. (1949) J. Am. Chem. Soc. 21:1150; Ireland et al. (1973) J. Am. Chem. Soc. 94:5897; Denmark et al. (1982) J. Am. Chem. Soc. 104:4972; Wilson et al. (1984) J. Org. Chem. 49:722; Buchi et al. (1985) J. Org. Chem. 50:4664; and Alker et al. (1990) J. Chem. Soc. Perkins Trans. 1, 1623). Despite its prolific use in chemical synthesis, very few examples of catalytic Claisen variants have been reported. See Vedejs et al. (1994) J. Am. Chem. Soc. 116:579, pertaining to protic acid (e.g., toluenesulfonic acid) catalysis of a Michael addition reaction, in turn initiating an aza-Claisen rearrangement. See also Saito et al. (1996) Synlett, 720, which describes the use of an aluminum catalyst, aluminum tris(4-bromo-2,6-diphenylphenoxide), in the Claisen rearrangement of allyl vinyl ethers.
In 1978, Bellus and Malherbe reported a ketene-Claisen reaction, in which treatment of an allyl ether with dichloroketene was found to result in the formation of a 1,3-dipolar allyl vinyl ether, which subsequently underwent [3,3]-bond reorganization, as follows: 
(Malherbe et al. (1978) Helv. Chim. Acta 61:3096; Malherbe et al. (1983) J. Org. Chem. 48:860). Subsequently, others have demonstrated utility of tertiary allylic amines in analogous [3,3]-sigmatropic rearrangement reactions. Edstrom et al. (1991) J. Am. Chem. Soc. 113:6690; Kunng et al. (1983) J. Org. Chem. 48:4262; Maruya et al. (1992) J. Chem. Soc., Perkin Trans, 1617; Vedejs et al., supra; Diederich et al. (1995) Angew Chem., Int. Ed. Engl. 34:1026; Deur et al. (1996) J. Org. Chem. 61:2871).
The aforementioned reactions are limited because of the ketene reactant used, as ketenes are highly unstable compounds. Furthermore, prior syntheses are generally not enantioselective; those who have attempted enantioselective Claisen rearrangements have met with substantial difficulties. For example, Corey et al. (1996) J. Am. Chem. Soc. 118:1229, developed an enantioselective Claisen reaction of an allylic ester, but the synthesis was not catalytic and required a reaction time of fourteen days. Yamamoto et al. (1995) J. Am. Chem. Soc. 117:1165, also developed an enantioselective Claisen reaction for rearrangement of an allylic vinyl ether, but the synthesis required stoichiometric quantities of an aluminum promoter.
Accordingly, there is a need in the art for an improved Claisen reaction that proceeds quickly, can be conducted as a xe2x80x9cone-potxe2x80x9d synthesis, is activated using catalytic quantities of a catalytic composition, and can be used to produce chiral products in enantiomerically pure form.
It is therefore a primary object of the invention to provide an improved Claisen reaction which addresses the aforementioned need in the art.
It is another object of the invention to provide a method for conducting a Claisen rearrangement reaction by reacting an allylic compound with an acid chloride in the presence of a Lewis acid catalyst composition.
It is still another object of the invention to provide such a method wherein the allylic compound is an allylic tertiary amine.
It is yet another object of the invention to provide such a method wherein one of the reactants is covalently linked, either directly or indirectly, to the surface of a solid support.
It is a further object of the invention to provide such a method wherein the position and/or size of substituents on the allylic reactant determine the stereochemistry of the reaction product.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one embodiment, then, the invention provides a method for conducting a Claisen rearrangement reaction via Lewis acid catalysis. The method involves reaction of an acid chloride with an allylic reactant (typically an allylic amine, an allylic ether, or an allylic thioether) in the presence of a Lewis acid catalyst composition comprised of two catalyst components, a first component composed of a Lewis acid, and a second component composed of a base, either a tertiary amine or a non-nitrogenous base. The reaction is conducted under inert, nonaqueous conditions at a temperature typically in the range of approximately xe2x88x92110xc2x0 C. to 200xc2x0 C., and can give rise to a nonracemic, chiral product. The reaction is represented in Scheme 1: 
In compounds (I), (II) and (III), the various substituents are as follows:
R1, R2, R3, R4, R5 and R6 are independently selected from the group consisting of hydrido, halo, hydroxyl, sulfhydryl, amino, substituted amino, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl;
Z is N, O or S;
n is zero or 1, with the proviso that when Z is N, n is 1, and when Z is O or S, n is zero; and
Q1 and Q2 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, or, when Z is N and n is 1, Q1 and Q2 may be joined together in a ring structure, generally a five- or six-membered cyclic group, or may together with Z form an azide xe2x80x94N3.
The stereochemistry of the product is controlled by the position and/or size of the substituents R2, R3, R4 and R5 on the allylic reactant. The process enables preparation of a wide variety of stereospecific compounds useful, for example, as starting materials in the synthesis of natural products and polymers, as pharmaceutical agents, as agrochemical agents, and as in combinatorial processes wherein arrays of chemical reactions are carried out in parallel on a solid support.